The transdermal administration of drugs in order to obtain systemic effects has gained increasing recognition in recent years as being a feasible mode for parenteral administration. More and more transdermal administration is being used for delivery of low molecular weight drugs, i.e., small size, drugs. The usual mode of transdermal delivery is through passive diffusional transport of the drug across the skin barrier. The scopolamine patch, the oestradiol patch and the nitroglycerin patch to which this mode of administration has been applied all contain low molecular weight drugs which are lipophilic (hydrophobic) in character.
However, passive transdermal delivery is not well suited to, and may not even be possible for drugs which are low in skin permeability. Unfortunately, such drugs include pharmacologically active hydrophilic peptide compounds, notably insulin.
In order to obviate the limitations on passive forms of transdermal delivery, the art has considered iontophoresis for systemic delivery of ionizing hydrophilic drugs. Iontophoresis may be described as being the transfer of solutes through a biologic membrane under the influence of an electrical field. Iontophoresis has been considered for administering insulin.
Transport through the skin by iontophoresis is believed to occur primarily through aqueous filled pores in the skin, e.g., sweat ducts. Since the net polarity of the pores in human skin is negative at neutral pH, delivery of positively charged molecules therethrough can be facilitated by application of an electrical current. However, the mean size of these pores is believed to be in the order of about 20 Angstrom, and, therefore the iontophoretic flow of a pharmacologically active compound through the skin in amounts adequate for the medical needs to be served by such compound is most feasible if the molecule of the compound is about 20 .ANG. in diameter or smaller.
The efforts made by the art, heretofore, to administer insulin through iontophoresis have been without great success. See Stephen et al. "Potential novel methods for insulin administration: I. Iontophoresis", Biomed. Biochim. Acta 43 (1984) 5, 553-558. Stephen et al. attributed their failure to force insulin across the skin barrier in pharmacologically adequate amounts to the relatively large size of the hexamer form of the insulin molecules (in solution). Stephen et al. postulated that a more strongly ionized predominantly monomeric form of insulin might successfully be administered transdermally by iontophoresis.
Subsequent to the work of Stephen et al. other investigators have reported achieving a more successful transdermal transport of human insulin by iontophoresis, see Meyer et al., "Transdermal Delivery of Human Insulin to Albino Rabbits Using Electrical Current", The American Journal of Medical Sciences, May 1989, Vol. 297, No. 5, pp. 321-325 and Ovais Siddiqui et al., "Facilitated Transdermal of Insulin", Journal of Pharmaceutical sciences, vol. 76, No. 4, Apr. 1987, pp. 341-345.
In the treatment of diabetes, injection or infusion of a predetermined quantity of insulin is presently required in order to maintain a therapeutically effective level of insulin in the blood. Due to the discomfort of the several daily injections of insulin that typically are administered, much effort has been expanded by the art over the years to find an administration route for insulin, other than through injection. Transdermal iontophoretic delivery offers the potential for being a superior route for administration of insulin. However, molecules of the usual insulin compound administered, e.g., the porcine insulin or human insulin, that heretofore has been conventional in the pharmaceutical compositions, is present in solution in such compositions in an associated form, notably as dimers and hexamers, the latter being the predominant association species.
The insulin hexamer has the shape of a slightly flattened sphere. The diameter of the insulin hexamer is approximately 50 .ANG., which diameter is believed to be too large for transdermal delivery (through the pores in the skin) in sufficient quantities to generate the therapeutically needed blood levels of insulin.
However, monomeric insulin analogues would have a smaller diameter and adequate dosage levels of such insulin compounds might be driven across the skin barrier through iontophoresis in therapeutically effective amounts.